Systemic Therapy of HER2-positive Breast Cancer

Tanja Cufer, MD, PhDUniversity Clinic Golnik,

Medical Faculty Ljubljana, Slovenia

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Adjuvant HER2-directed Therapy

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Adjuvant Trastuzumab Improves DFS and OS in HER+ EBC

Trial Study Design

No. of Patients Treatment Arm

DFSAbsolute valuesHR (95% CI; p)

OSAbsolute valuesHR (95% CI; p)

HERAPiccart-Gebhart M, et al. NEJM 2015 Cameron D, et al. Lancet 2017.

Phase 3

1,698 Observation 11-year DFS: 63.0% 12-year OS: 72.9%

1,703 Sequential trastuzumab 1 yr 11-year DFS: 69.3%0.76 (0.68-0.86; <0.0001)

12-year OS: 79.4%0.74 (0.64-0.86; <0.0001)

1,701 Sequential trastuzumab 2 yrs 11-year DFS: 68.5%0.77 (0.69-0.87; <0.0001)

12-year OS: 79.5%0.72 (0.62-0.83; <0.0001)

NCCTG N9831 and NSABP-B31Perez EA, et al. J Clin Oncol 2014.

Phase 32,018 CT 8-year DFS: 62.0% 8-year OS: 75.2%

2,028 CT +trastuzumab 1 yr

8-year DFS: 73.7%0.60 (0.53-0.68; <0.001

8-year OS: 84.0%0.63 (0.54-0.73; <0.001)

BCIRG 006Slamon DJ, et al. SABCS 2015.

Phase 3

1,073 AC -> T 10-year DFS: 67.9% 10-year OS: 78.7%

1,074 AC -> TH -> trastuzumab 1 yr 10-year DFS: 74.6%0.72 (0.62-0.85; <0.0001)

10-year OS: 85.9%0.63 (0.62-0.79; <0.0001)

1,075 TCH -> trastuzumab 1 yr 10-year DFS: 73.0%0.77 (0.65-0.90; 0.0011)

10-year OS: 83.3%0.76 (0.62-0.93; 0.0075)

Adjuvant trastuzumab 1 year: risk of relapse (DFS) by 23%-40%; with absolute benefit between 6%-12%. risk of death (OS) by 24%-37%; with absolute benefit between 7%-9%.

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Subgroup (no. patients) HR (95% CI)Nodal status

Not assessed (neoadjuvant chemotherapy) (372) 0.66 (0.43, 1.00)Negative (1099) 0.59 (0.39, 0.91)1–3 positive nodes (976) 0.61 (0.43, 0.87)≥4 positive nodes (953) 0.64 (0.49, 0.83)

Hormone receptor statusER negative + PgR negative (1627)ER negative + PgR positive (172)ER positive + PgR negative (460)ER positive + PgR positive (984)

All patients (3401)

Favours observationFavours trastuzumab

0.0 0.5 1.0 1.5

Disease-free survival (DFS) HR

0.63 (0.50, 0.78)0.77 (0.34, 1.74)0.82 (0.50, 1.34)0.63 (0.43, 0.93)

0.64 (0.54, 0.76)

Untch, et al. Ann Oncol 2008.

Trastuzumab is Effective Regardless Nodal and/or HR Status: HERA Trial

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Concurrent Trastuzumab Performs Better than Sequential: NCCTG N9831Trial

Perez, et al. Cancer Res 2009.

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Benefit of Trastuzumab in Small ≤ 2cm N0 Disease: Meta-Analysis

O’Sullivan C, et al. J Clin Oncol 2015

HR +

HR -

Trastuzumab is recommended for patients with T1c (> 1cm) tumors, while its role in tumors ≤ 1 cm is still debatable.

Small number (n=75) of T1a/b (≤ 1 cm) pts (n=75) included!

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Cardiac Safety of 1 year Adjuvant HER2-directed TherapyTrial Arm Any CHF (%) Any LVEF drop (%)

HERA, de Azambuja, et al. (2014) ChemoChemo T 1y

00.8

0.97.2

NSABP B-31, Romond, et al. (2012) AC PAC PT

1.23.8

NR12.0

NCCTG N9831, Advani, et al. (2016) AC PAC P TAC PT

0.92.63.5

9.616.723.8

BCIRG 006, Slamon, et al. (2015) AC DAC DTDCarboT

0.82.00.4

11.219.19.4

APT, Tolaney, et al. (2015) PT 0.5 3.2

ALLTO, Piccart M, et al. (2016) Chemo T 1yChemo T Lapa 1yChemo T + Lapa 1y

1.0<1.01.0

5.03.05.0

APHINITY, von Von Minckwitz, et al. (2017)

Chemo T 1yChemo T + Pertuz 1y

0.30.7

2.82.7

Risk factors for CHF: low LVEF, age, obesity, hypertension. LVEF is mandatory before initiation of trastuzumab and during treatment.

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Escalation and De-escalation of Adjuvant Anti-HER2 Therapy

Adoped from Lambertini M, et al. Expert Rev Cancer Ther 2017.

Non-anthracycline-based CT BCIRG 006: TCH regimen (positive) APT: weekly P + H (positive)

Reducing duration of adjuvant H PHARE: H for 6 months (negative) HORG trial: H for 6 months (negative) SHORT-HER: H for 3 months (negative) PERSEPHONE: H for 6 months (positive) SOLD: H for 9 weeks (on-going)

„CT-free“ regimen ATEMPT: T-DM1 (on-going)

ANTHRACYCLINE AND TAXANE BASED CHEMOTHERAPY WITH TRASTUZUMAB

FOR ONE YEAR

Escalating targeted agents BETH: H + Bevacizumab (negative) ExteNET: H -> neratinib (positive) ALTTO: H -> L or H+L (negative) APHINITY: H + pertuzumab (positive) KAITLIN: T-DM1 + pertuzumab (on-going)

Prolonging duration of adjuvant H HERA: H for 2 years (negative)

Adjuvant treatment if no pCR KATHERINE: T-DM1 (positive)

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Escalating HER2-directed Adjuvant TherapyTrial Study

DesignNo. of Patients Treatment Arm

DFSAbsolute valuesHR (95% CI; p)

OSAbsolute valuesHR (95% CI; p)

Longer duration of HER2-directed therapy

HERACameron D, et al. Lancet 2017.

Phase 31,552 CT + trastuzumab 1 yr 10-year DFS: 73.9% 12-year OS: 86.1%

1,553 CT + trastuzumab 2 yrs 10-year DFS: 73.1%1.02 (0.89-1.17; 0.796)

12-year OS: 83.6%1.01 (0.84-1.21; 0.916)

ExteNETChan A, et al. Lancet Oncol 2016.

Phase 31,420 CT + trastuzumab 1 yr + placebo

for another year2-years IDFS: 91.6% NR

1,420 CT + trastuzumab 1 yr + neratinib for another 1 yr

2-years IDFS: 93.9%0.67 (0.50-0.91; 0.0091)

NR

Dual HER2-directed therapy

ALTTOPiccart-Gebhart M, et al. J Clin Oncol 2016.Moreno-Asptia A et al., ASCO 2017 Abstr 502.

Phase 3

2,097 CT + trastuzumab 1 year 6-year DFS: 82.0% 6-year OS: 91.0%

2,100 CT + lapatinib 1 year 4-year DFS: 82.0%1.34 (1.13-1.60; <0.0005)

4-year OS: 93.0%1.36 (1.09-1.72; 0.007)

2,091 CT + trastuzumab -> lapatinibfor 1 year

6-year DFS: 84.0%0.93 (0.81-1.1.08; ns)

6-year OS: 92.0%0.88 (0.71-1.08; ns)

2,093 CT + trastuzumab + lapatinib for 1 year

6-year DFS: 85.0%0.86 (0.74-1.00; ns)

6-year OS: 93.0%0.86 (0.70-1.06; ns)

APHINITYvon Minckwitz G et al., NEJM 2017

Phase 3

2405 CT + trastuzumab + placebo for 1 year

3-year iDFS:93.2% NR

2400 CT + trastuzumab + pertuzumab for 1 year

3-year iDFS: 94.1%0.81 (0.68- 1.00; 0.0045)

NRESO-E

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ExteNET: 1 year Neratinib after 1 year of Trastuzumab vs 1 year Trastuzumab alone

Chan A, et al. Lancet Oncology 2016.

Positive DFS data persist with longer FU (5-year DFS, Martin M, Lancet Oncol 2017).

OS data are still pending! Effect due to treatment extension or to HR and

HER2 signaling co-targeting?

Substantial toxicity (40% G3/4 diarrhea) Anti-diarrhea prophylaxis may be used

(CONTROL trial, Hurwitz S, et al. Cancer Res 2018).

Subsets HR iDFSNode-negative 0.83 (ns)1 – 3+ nodes 0.75 (ns)4+ nodes 0.67*ER+ 0.60*ER- 0.95 (ns)

5yr DFS absolute benefit = 2.6%

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APHINITY: 1 year Trastuzumab plus Pertuzumab vs 1 year Trastuzumab plus Placebo

von Minckwitz G, et al. N Engl J Med 2017.

3yr iDFS absolute benefit = 0.9%

Number needed to treat: 112

Expected: 89.2%

Statistically significant, but, is it clinically meaningful ?

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HR = 0.39, P<.001 HR = .58, P = .001 HR = 0.25, P<.001

Neoadjuvant Therapy: In vivo Testing of Therapy & Risk Stratification Testing based on pCR

Cortazar P, et al. Lancet 2014.

Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC): Association between pCR and EFS in HER2-Positive Subtype

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KATHERINE: Adjuvant T-DM1 vs Trastuzumab in Residual Invasive Disease after Neoadjuvant Cht and HER2-directed Therapy

Overall survival data are still immature!

von Minckwitz G, et al. N Engl J Med 2018.

3yr iDFS absolute benefit = 11.3%

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KATHERINE: Adjuvant TD-M1 vs Trastuzumab in Residual Invasive Disease after Neoadjuvant Cht and HER2-directed Therapy

TD-M1 benefit was observed regardless• Initial clinical status• HR status• pT/pN status

von Minckwitz G et al. N Engl J Med 2018.

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De-escalating HER2-directed Adjuvant Therapy

Trial Study Design

No. of patients

Treatment Arm

DFSAbsolute ValuesHR (95% CI; p)

OSAbsolute ValuesHR (95% CI; p)

Non-anthracycline- based Cht

BCIRG 006Slamon DJ, et al. SABCS, 2015.

Phase 3 1,073 AC -> T 10-year DFS: 67.9%

10-year OS: 78.7%

1,074 AC -> TH -> Trastuzumab for 1 year

10-year DFS: 74.6% 0.72 (0.62-0.85; <0.0001)

10-year OS: 85.9% 0.63 (0.51-0.79; <0.0001)

1,075 TCH -> Trastuzumab for 1 year

10-year DFS: 73.0% 0.65 (0.65-0.90; <0.0011)

10-year OS: 83.3%0.76 (0.62-0.93; <0.0075)

APTTolaney SM, et al. N Engl J Med 2015;ASCO 2017, Abstr 511

Phase 2(T1/2 N0)

406 Weekly paclitaxel x 12 + Trastuzumab for 1 year

7-year iDFS: 93.3%

7-year OS: 95.0%

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De-escalating HER2-directed Adjuvant Therapy

TrialNo. of

patients Treatment ArmDFSAbsolute ValuesHR (95% CI; p)

OSAbsolute ValuesHR (95% CI; p)

Cardiac Events Shorter vs Longer Trastuzumab

Shorter duration of adjuvant Trastuzumab

PHARE Phase 3Pivot X, et al. Lancet Oncol 2013.

1690 CT + trastuzumab for 1 year 2-year: 93.8% NR 5.7%*

1690 CT + trastuzumab for 6 months

2-year: 91.1% 1.28 (1.05-1.56; 0.29)

NR1.46 (1.06-2.01; 0.03)

1.9%

HORG Phase 3Mavroudis D, et al. Ann Oncol 2015.

241 ddFEC -> ddDocetaxel + trastuzumab for 1 year

3-year: 95.7% NR 2 cases

240 ddFEC -> ddDocetaxel + trastuzumab for 6 months

3-year: 93.3% 1.57 (0.86-2.10; 0.137)

NR1.45 (0.57-3.67; 0.438)

0 cases

Short-HER Phase 3Conte PF, et al., ASCO 2017, Abstr501.

627 CT + trastuzumab for 1 year 5-year: 87.5.% NR 16%*

626 CT + trastuzumab for 9 weeks

5-year: 85.4% 1.15 (0.91-1.46; ns)

NR 6%

PERSEPHONE Phase 3Earl H, et al. ASCO 2018, Abstr 506

2045 CT + trastuzumab for 1 year 4-year: 89.8% NR 12%*

2043 CT + trastuzumab for 6 months

4-year: 89.4%1.07 (0.93-1.24; 0.01)

NR 9%

SOLD Phase 3Joensuu H, et al. JAMA Oncol 2018

1089 CT + trastuzumab for 1 year 5-year: 90.5% NR 4%

1085 CT + trastuzumab for 9 weeks

5-year: 88.0%1.30 (1.12 – 1.72; ns)

NR 2%ESO-ESMO E

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Selection of the “Non-inferiority margin”

Phare

PERSEPHONEHORG

Short-HER

1.05 1.561.15

1.28

0.86 2.101.53

1.57

1.91 1.461.29

1.15

1.12 1.721.30

1.39SOLD

0.93 1.241.31

1.07

Non -inferiority claim NOT supported by trial results

Non-inferiority claim supported by trial results

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PERSEPHONE and SHORT-HER Subgroups AnalysisSHORT-HER: Subgroups for which 6 m might be non-inferior

Earl H, et al ASCO 2018, Abstr 506; Conte PF, et al. ASCO 2017, Abstr 501.

PERSEPHONE: Subgroups for which 12 m might be superior

ER-

Taxane-based

Stage I, II

N0-1

Shorter trastuzumab treatment duration might be equally effective in low stage, ER + disease.

However, in all other scenarios 1 year of trastuzumab remains the gold standard!

No inferiority margin 1.29

No inferiority margin 1.31 ESO-ESMO E

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HER2- directed Therapy for Advanced Breast Cancer (ABC)

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Cardoso F, et al The Breast 2011.

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HER2+ Advanced Breast Cancer: Currents Standards of Care in 2019

Adopted from Piccart M, SABC Symposium 2017; Cardoso F, et al. Ann Oncol 2016.

First line Second line* Later lines** . . . .

Pertuzumab Lapatinib

Trastuzumab

Lapatinib

TrastuzumabTrastuzumab

Taxane Vinorelbine CapecitabineTDM1

Superior to trastuzumab + docetaxel

(CLEOPATRA)

Superior to capecitabine + lapatinib

(EMILIA) or to physicians choice

(TH3RESA)

Pertuzumab

Capecitabine

Trastuzumab

Superior to lapatinib alone (EGF 104900)

Superior to lapatinib plus capecitabine

(MA.31)

* In pts with DFI ≤ 12 mos start as first line; ** Combination of trastuzumab plus either capecitabine, eribulin, gemciatbine, platinum agents or metronomic Cht might be used as well as per ABC3!ESO-E

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Swain S, et al. NEJM 2015.

CLEOPATRA: First-line Trastuzumab and Docetaxel +/-Pertuzumab in HER2+ MBC

Pertuzumab + trastuzumab+docetaxel

Placebo + trastuzumab+docetaxel

Hazard ratio P-value

ORR1 80.2% 69.3% 0.0001

PFS2 18.7 months 12.4 months 0.68 <0.0001

OS2 56.5 months 40.8 months 0.66 0.0001

Long term cardiac safety maintained, with favorable LVEF and CHF in experimental arm !ESO-E

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Verma S, et al. NEJM 2012.

13www.esmo2012.org

Progression-Free Survival by Independent Review

496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0

Cap + LapT-DM1

No. at risk by independent review:

Median (months)

No. of events

Cap + Lap 6.4 304T-DM1 9.6 265Stratified HR=0.650 (95% CI, 0.55, 0.77)

P<0.0001

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Prop

ortio

n pr

ogre

ssio

n-fr

ee

Time (months)

Unstratified HR=0.66 (P<0.0001). 16www.esmo2012.org

Overall Survival: Confirmatory Analysis

496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5

Cap + LapT-DM1

No. at risk: Time (months)

78.4% 64.7%

51.8%

85.2%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 360.0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n su

rviv

ing

Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).

Median (months) No. of eventsCap + Lap 25.1 182T-DM1 30.9 149Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006

Efficacy stopping boundary P=0.0037 or HR=0.727

T-DM1 Lapatinib + capecitabine Hazard ratio P-valuePFS 9.6 months 4.6 months 0.65 <0.001OS 30.9 months 25.1 months 0.68 <0.001

EMILIA: T-DM1 vs Lapatinib Plus Capecitabine in HER+ MBC

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HER2+ Advanced Breast Cancer: Standards of Care for “Triple Positive “ Disease in 2019

First line Second line Later lines . . . .

Pertuzumab Lapatinib

Trastuzumab

Lapatinib

TrastuzumabTrastuzumab

EndocrineTherapy

EndocrineTherapy

VinorelbineTDM1

Superior to trastuzumab + ET

(PERTAIN); Induction Cht in 57%

Superior to lapatinib or trastuzumab + ET

(ALTERNATIVE)

Trastuzumab

Adopted from Piccart M, SABC Symposium 2017. Cardoso F, et al. Ann Oncol 2016.

Superior to lapatinib alone (EGF 104900)

• Trials comparing HER2 plus ET vs HER2 plus Cht in ABC are ongoing (Detect V, CHEVENDO, PERNETTA,…)• Despite absence of EBD, HER2 plus ET might be considered as maintenance therapy as per ABC3.

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Trial Treatment arm No. ptsMedian

PFS(months)

Overall Response Rate (ORR)

Overall Survival (months)

First-line setting PERTAIN*Arpino G et al., SABCS 2016.

AI + Trastuzumab +/-

Pertuzumab**

258 15.8

18.9*

56%

63%

NR

Second-line settingALTERNATIVEGradishar WJ et al., ASCO 2017, Abstr1004.

AI + TrastuzumabAI + Lapatinib

AI + Trastuzumab + Lapatinib

355 5.78.3

11.0*

14%19%32%*

NR

HER2- directed plus ET in First-line Therapy of HR+/HER2+, ”Triple positive” MBC

Gradishar WJ, et al. ASCO 2017, Abstr 1004.

Dual HER2 blockade plus ET performs better than mono HER2 plus ET; therefore, it is a reasonable option in selected HR+/HER2+ patients, used as induction or as maintenance therapy.

* PERTAIN: Induction Cht in 57%.

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Treatment of CNS Metastases in HER2+ MBC

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Trastuzumab Improves Survival in Patients with CNS Disease: Retrospective Analysis

Kirsch DG, et al. JCO 2005

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OS (ITT population)

Surv

ival

(%

)

Time from randomisation (months)Subjects at riskLap + CapTras + Cap

271 194 129 79 48 27 7269 207 140 97 61 29 6 1

Lap + Cap (N=271) Tras + Cap (N=269)

Median OS, months 22.7 27.3

Hazard ratio (95% CI) 1.34 (0.95, 1.90)

Stratified log-rank p-value 0.095

Early closure!

Low number of brain metastases.

Trastuzumab + capecitabinebetter OS

CEREBEL: Capecitabine plus Lapatinib or Trastuzumab in HER2+ MBC without CNS mets

Lapatinib + capecitabine

(N=251)Trastuzumab + capecitabine

(N=250)OR

(95% CI) P-value

CNS at first site of relapse, n (%) 8 (3) 12 (5) 0.65(0.26-1.63) 0.360

Incidence of CNS progression at any time, n (%) 17 (7) 15 (6) 1.14(0.52-2.51) 0.8646

Time to first CNS progression, median (range) 5.7 (2-27) 4.4 (2-27) - -

Pivot X, et al. J Clin Oncol 2015.

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Awada A, et al. JAMA Oncology 2016.

NEfERT-T phase 2: Neratinib plus Paclitaxel vs Trastuzumab plus Paclitaxel

Ongoing NALA phase 3 trial (NCT 01808573) is evaluating neratinib plus capecitabine vs lapatinib plus capecitabine in HER2-pretreated MBC; with time to intervention for symptomatic CNS as secondary end-point. ESO-E

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Novel Treatment Strategies for HER2+ Breast Cancer in Clinical Research

New predictive markers for better tailoring of HER2-directed therapy are urgently needed! So far, we only have additional prognostic markers (HER2 mRNA, PIK3CA, TIL), while HER2

status remains the only predictive biomarker. At least we should take into consideration that triple positive breast cancer is a distinctive subtype!

Novel HER2-directed AgentsAntibody Drug Conjugates (Trastuzumab deruxtecan, SYD 985)Novel Antibodies (Margetuximab, SOPHIA trial)Novel TKIs (Neratinib, Pyrotinib, Tucatinib)

Novel CombinationsAnti-HER2 + CDK 4/6 Inhibitors (palbociclib plus trastuzumab, active in HR+ subset) Anti-HER2 + PD-1/PD-L1 Inhibitors (T-DM1 plus atezolizumabactive in PD-L1 positive subset)Anti-HER2 + PI3K Inhibitors

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